Rat 동물모델에서 Tofacitinib의 용량의존적 Parmacokinetics : 낮은 생체 이용률에 간과 위장관 초회통과효과의 영향
Dose-Dependent Pharmacokinetics of Tofacitinib in Rats: Influence of Hepatic and Gastrointestinal First-Pass Effect on Low Bioavailability
- 주제(키워드) Tofacitinib , Dose-dependent pharmacokinetics , First-pass effect , Low-bioavailability
- 발행기관 아주대학교
- 지도교수 김소희
- 발행년도 2018
- 학위수여년월 2018. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000027538
- 본문언어 한국어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Tofacitinib was indicated dependence on the dose increase in both cases of intravenous administration and oral administration. One of the dose-dependent pharmacokinetic parameter, the area under the plasma tofacitinib concentration-time curve from time zero to infinity (AUC0-∞), was meaningfully higher at 50 mg/kg dose of tofacitinib than at 5, 10 and 20 mg/kg (283, 342, 381 and 776 ug∙min/mL for 5, 10, 20 and 50 mg/kg, respectively, dose-normalized at 10 mg/kg) in intravenous administration study. In oral administration study, also the AUC0-∞ was meaningfully higher at 100 mg/kg dose of tofacitinib than at 10, 20 and 50 mg/kg (99.4, 151, 228 and 413 ug∙min/mL for 10, 20, 50 and 100 mg/kg, respectively, dose-normalized at 10 mg/kg). The absolute oral bioavailability (F) was about 29.1% at 10 mg/kg dose of todacitinib in rat. For first-pass effect study, the AUC0-∞ values were compared between these group which administered by intravenous, intraportal, intraportal, intraduodenal and intragastric route, respectively. The hepatic first-pass effect of tofacitinib was calculated about 41.9% and the intestinal first-pass effect of tofacitinib was calculated about 49.2% using rat model. The gastric first-pass effect was negligible. Consequently, the reasons of nonperfect F value were evaluated to be owing to the high hepatic and intestinal first-pass effect.
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I. INTRODUCTION 1
II. METHOD 3
A. Chemicals 3
B. Animals 3
C. Evaluate pharmacokinetics of tofacitinib after intravenous and oral administration in rat model 3
D. Measurement of tofacitinib concentration in rat tissues (organs) after intravenous administration 4
E. Evaluation of hepatic first-pass effect of tofacitinib 5
F. Evaluation of gastric and intestinal first-pass effect of tofacitinib 5
G. Biliary excretion of tofacitinib using rat model 6
H. HPLC analysis of tofacitinib 6
I. Pharmacokinetics analysis 7
J. Statistical analysis 7
III. RESULTS 9
A. Pharmacokinetics of tofacitinib after intravenous administration using rat model 9
B. Pharmacokinetics of tofacitinib after oral administration using rat model 13
C. Measurement of tofacitinib concentration in rat tissues (organs) after intravenous administration 16
D. Evaluation of hepatic first-pass effect of tofacitinib 18
E. Evaluation of gastric and intestinal first-pass effect of tofacitinib 21
F. Biliary excretion of tofacitinib using rat model 24
IV. DISCUSSION 25
V. CONCLUSION 27
REFERENCES 28
KOREAN ABSTRACT 30
